GO Fight Against Malaria

In very rare cases, blood transfusions can also transmit malaria infections, but female mosquitoes are the main culprit.
After a person has become infected with malaria, "chemotherapeutic approaches" are employed (that is, a drug or a combination of different drugs is used to cure the malaria infection). There are many different drugs that can be used to cure malaria infections; however, the parasites that cause malaria eventually evolve “drug resistance” against the specific chemicals that are used to eliminate the parasites (see the FAQ below on “multi-drug-resistant mutant superbugs”). For example, in the past the drug chloroquine was very useful for curing malaria infections, but the Plasmodium parasites eventually evolved drug resistance against chloroquine. Later, the dual drug combination of sulfadoxine plus pyrimethamine was developed. For several years it was very useful for curing malaria infections, and it helped save millions of lives. But then the Plasmodium parasites evolved resistance to this dual drug combination, too. Since resistance to sulfadoxine plus pyrimethamine started becoming very prevalent, the World Health Organization now recommends that artemisinin-based combination therapies (“ACTs”) be used to treat malaria infections. Unfortunately, Plasmodium falciparum parasites that are able to resist treatment with artemisinin, and its derivatives, have recently started to appear at the Thai-Cambodian border. The drug resistance phenomenon is the reason why discovering and developing new drugs that can eliminate multi-drug-resistant malaria infections is a global health necessity, and it’s the reason why we created the GO Fight Against Malaria project.
Malaria thrives in tropical and subtropical regions. Malaria infections are found in at least 106 different countries. It predominantly infects people in Africa, South-East Asia, and South America. However, in this era of globalization, it affects almost all sub-populations of the world, either physically, mentally, or monetarily. Millions of people from developed countries visit or work in malaria-infested regions each year.
When an infected female mosquito bites someone’s skin, the Plasmodium parasite is injected. The parasite quickly invades liver cells (within a matter of minutes after it was injected). The parasite hides in the liver cells, where it undergoes asexual multiplication. This stage in the liver tends to last for eight to thirty days, during which the symptoms of malaria do not yet appear. The parasites escape the liver by rupturing the infected cells. The parasites then invade red blood cells, where they continue to undergo asexual multiplication. When these malaria parasites replicate themselves in red blood cells (which the parasites use for food and then burst), the symptoms of malaria appear (see the FAQ above on the symptoms of malaria). If another mosquito then feeds on that infected person’s blood, that mosquito becomes infected. Plasmodium parasites can only sexually reproduce when they are inside a mosquito.
GO Fight Against Malaria is a project of the Olson laboratory (http://mgl.scripps.edu). The project uses distributed computing to help accelerate research on the discovery of new drugs which can cure infections of multi-drug-resistant mutant “superbugs” of Plasmodium falciparum, the parasite that causes the deadliest form of malaria.
Detailed, step-by-step instructions are available at: http://www.worldcommunitygrid.org/reg/viewRegister.do. After installing BOINC and registering to become a member of World Community Grid, your computing device is then automatically put to work on these projects, and you can continue using your device as usual.
This project uses AutoDock 4.2 and the new AutoDock Vina computer software to evaluate how well each candidate compound (molecule) attaches ("docks" or "binds") against a malarial target (usually a protein molecule.) Millions of candidate compounds will be tested against 14 different molecular drug targets from the malaria parasite in order to discover new compounds that can block (inhibit) the activity of these multi-drug-resistant mutant superbugs. These candidates will be tested by docking flexible models of them against 3-D, atomic-scale models of different protein drug targets from the malaria parasite, to predict (a) how tightly these compounds might be able to bind, (b) where these compounds prefer to bind on the molecular target, and (c) what specific interactions are formed between the candidate and the drug target. In other words, these calculations will be used to predict the affinity/potency of the compound, the location where it binds on the protein molecule, and the mode it uses to potentially disable the target. Compounds that can bind tightly to the right regions of particular proteins from the malaria parasite have the potential to “gum up” the parasite’s machinery and, thus, help advance the discovery of new types of drugs to cure malaria.
These are two different types of “docking” programs, which allow us to computationally search for new compounds that might be able to bind to and block the activity of molecular drug targets from the malaria parasite. Both of these docking programs were created and developed by the Olson lab at The Scripps Research Institute (http://mgl.scripps.edu).
AutoDock Vina also uses pre-calculated grid maps (which are generated internally, instead of using a separate program, such as autogrid). Vina also uses flexible models of the small molecules, and it also treats the docking process as a stochastic global optimization of the scoring function. But Vina utilizes a different scoring function and a different search algorithm than AutoDock, and Vina’s search process is guided by the gradients in the energetic landscape of the target protein (unlike AutoDock4.2).
More information about malaria can be found at the World Health Organization’s website, the Medicines for Malaria Venture website, and on Wikipedia.